It is a rare study I read that makes me want to literally stop everything else I am doing and write a blog post about it.  It is a dreary, gray Sunday morning and I was just catching up on some backlogged journal reading when I picked up the August 2010 issue of Antimicrobial Agents and Chemotherapy.  I came across a paper out of the University of Antioquia in Medellin, Columbia by Omar Vesga and colleagues entitled “Generic Vancomycin Products Fail in vivo despite Being Pharmaceutical Equivalents of the Innovator” (PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20547818) .  Regular readers of this blog and the Handbook, and those who have attended my lectures, know that I have not been particularly kind to vancomycin given significant failure rates reported in numerous studies. This study might explain why there are so many failures.

Vancomycin was first developed by Eli Lilly after it was discovered as a fermentation product of Amycolatopsis orientalis found in a sample of dirt sent to Lilly from Borneo in 1955.  Early formulations had significant impurities which, along with lending the product a brown color, hence leading to its’ early moniker “Mississippi Mud”, also was felt to lead to significant adverse events.  Lilly eventually found ways to highly purify the product to the relatively safe drug we know today.  Apparently, those extra steps were kept secret until they were finally sold as recently as 2005.  I clearly remember a Lilly sales rep calling on me 20 some years ago when the drug first went generic.  He pulled out a vial of the newly generic vancomycin and it was sandy brown in color.  He then pulled out a vial of the brand named Vancocin and it was, indeed, Lilly white…pun intended.  His point was simply, “Doc, which would you rather have going into your patients’ vein?”  Of course, hospital formularies being the way they were/are we really did not have a choice as to which we wanted to use. 

Back to the Vesga study: The investigators studied 3 generic versions of vancomycin vs. the “innovator” product to determine concentrations and clinical efficacy via numerous techniques both in vitro and in an in vivo mouse model.  In my opinion this was an elegantly designed, complex study which used multiple techniques including time-kill curves (TKC), broth microdilution and a neutropenic mouse thigh infection model, along with others, while using different strains of S. aureus.  Their findings were fascinating!  To directly quote the Abstract:

 “Vancomycin generics were virtually undistinguishable from the innovator based on concentrations and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentration and TKC, and serum pharmacokinetics.  Despite such similarities, all generic products failed in vivo to kill S. aureus while the innovator displayed the expected bactericidal efficacy…” (Emphasis added) 

The authors conclude that the current standard of “pharmaceutical equivalence predicting therapeutic equivalence” is not true, at least for vancomycin.  They make it clear that they are not claiming that the tested generics were in any way poor quality.  They certainly met all of the current regulations governing the necessary equivalence to make it to the market.  But this study raises a number of questions:  Is this finding of pharmacologic equivalence not equaling clinical efficacy unique to vancomycin or could it be a factor in other generic antibiotics?  Could the universal use of generic vancomycin in hospital pharmacies account for the increasing clinical failures being seen not only in clinical trials but everyday practice?

I know that this title seems like I am tying in a number of fairly diverse topics but hear me out on this one.  I was browsing through USA Today while sitting in an airplane last week and came across a story whose title read “Safety Breaches at Surgery Centers”.  That, in and of itself was interesting enough to me but upon reading the story I learned that “A federal study finds many same day surgery centers – where patients get such things as foot operations (my emphasis added) and pain injections – have serious problems with infection control.”

This short piece in the paper was reporting on the results reported in a study published in the June 9, 2010 issue of the Journal of the American Medical Association by Schaefer MK, et al entitled “Infection Control Assessment of Ambulatory Surgical Centers.” Ambulatory surgical centers in 3 states were assessed specifically looking at hand hygiene, injection safety and medication handling, equipment reprocessing, environmental cleaning and handling of blood glucose monitoring equipment.  Despite the centers knowing that they were being observed 67.6% had at least one lapse.  Also of interest was the breakdown on numbers and types of procedures.  Almost a full 1/3 of all of the procedures performed at these surgi-centers were classified as “Podiatry”.  I did not find where the study differentiated lapses in infection control by types of procedure and, unlike the USA Today piece, the JAMA article did not specifically single out “foot operations”.

The reason for me reporting on this study, besides the public relations nightmare from the USA Today piece, is that I know many podiatric physicians have financial interest in an ambulatory surgical center.  All I can do is plead with you to maintain the absolute highest level of vigilance in your infection control practices.  This WILL come back and “bite” you if you do not.  After a report like this in a journal like JAMA you know that more regulations are not far behind!

Along the same vein, I sit on my hospital’s Infection Prevention and Control Committee.  At our most recent meeting the RN Infection Control Coordinator passed out an article which was a position paper from the Association for Professionals in Infection Control and Epidemiology (APIC) on safe injection practices:  Dolan SA, et al. APIC position paper: Safe injection, infusion and medication vial practices in health care. Am J Infect Control 2010, 38:167-72.  Why I found this particularly pertinent to what we do in lower extremity practice is that it discusses the use of multi-dose medication vials.  I have personally reviewed a few mal-practice cases of docs being sued for allegedly causing infection by using these vials.  Apparently, there is some controversy about how long one of these vials can be used. The United States Pharmacopeia (USP) requires that a multi dose vial must be disposed of 28 days after the initial stopper penetration unless the Product Insert states otherwise.  The Centers for Disease Control and Prevention (CDC), however, takes the stance that the bottle can be used until the manufacturers’ expiration date or if there are concerns about its sterility.

Taking these different opinions into account the APIC Guidelines suggests “…adhering to strict aseptic technique when accessing the vial, using a new sterile needle and a new sterile syringe for every access, removing all access devices from the vial, storing the vial in a clean protected location according to the manufacturer’s directions and ensuring that any vial whose sterility may be compromised is immediately discarded.”  I rather like one of their other comments and suggest to  you that, although not economically viable, and not currently “standard of care”, may be the best advice to protect your patient and yourself…”Use multi-dose medication vials for a single patient whenever possible…Infection transmission risk is reduced when multi-dose vials are dedicated to a single patient”.

I will be in Columbus, OH for the Region IV (Ohio) meeting to lecture on June 3, 2010.  I have been given the “Learning Lunch” spot from 12:00 to 1:30 and plan on covering a broad range of lower extremity infectious diseases topics including MRSA, antibiotic therapy for osteomyelitis and diabetic foot infections.

Prior to my session, I will be in the Exhibit Hall from 9:30 – 11:30 at the Data Trace Booth to sign copies of the Handbook, talk about this blog and just answer questions anyone might have about treating infections.

I hope to see folks there!

The following is from the text I sent to Podiatry Today Magazine for an upcoming feature they are planning on Innovations in Podiatry.  I really feel that molecular diagnosis of infection has the potential to change the way we diagnose and ultimately treat lower extremity infections.  The company I discuss in the article below, Diatherix, has a unique technology that allows the identification of up to 25 organisms from a single specimen and a single run of the test yielding results in just a few hours.  Just for full disclosure, although I have met with the CEO of the company to discuss the technology I have no financial interest or other conflicts at this time:

The current standard for making a bacteriologic diagnosis of a lower extremity infection is the use of a culture and sensitivity.   The problem with this test is that it may take several days to obtain a result while the patient has been placed on empiric antibiotic therapy that may be either too broad or too narrow spectrum.  Although Polymerase Chain Reaction (PCR), to look at the DNA of the organisms found on a specimen, has been used for a number of years to rapidly identify the bacteria, it has been limited mostly to reference laboratories and is hindered by usually only being able to identify one organism at a time.  This is changing with the use of Target Enriched Multiplex-PCR (Tem-PCR) which has the ability to identify up to 25 or more organisms with a single sample and to do it within just a few hours. A company based out of Huntsville, AL, Diatherix, is now commercializing this technology so that any physician in an office or wound center can order this test.  The clinician receives swabs and transfer materials, including overnight mailers from the company.  They take a specimen, as they would a standard C&S; place it in the mailer to Diatherix which receives it the next morning.  By that afternoon a result is communicated to the clinician including the identity of the organism, its relative frequency compared to other bacteria found in the specimen and any genetic markers for resistance, such as the presence of the mecA gene indicating MRSA.

By accurately identifying disease-producing pathogens early, Tem-PCR results can assist physicians in forming a more accurate diagnosis. This provides them the opportunity to accurately diagnosis the condition which leads to the appropriate treatment rather than treating empirically. By enabling physicians to link diagnostics to therapeutics, Tem-PCR results can assist by eliminating the inappropriate use of antibiotics eliminating unnecessary treatments, reducing the development of genetic drug resistance, potentially reducing cost of therapy and providing a better patient outcome.

The Tem-PCR technology provides multiplex amplification of genomic material from multiple pathogens with greatly increased sensitivity compared to standard multiplex PCR.  Standard multiplex PCR in general cannot amplify multiple pathogens in a single analysis due to each set of primers requiring differing optimum conditions for best amplification.  Tem-PCR works around this by essentially turning the multiplex into a singleplex reaction needing one primer set and one set of optimum conditions so that the best amplification can be obtained.  This allows more results from a single sample as a benefit of Tem-PCR over both singleplex PCR and qPCR (real time PCR).

Three significant benefits of producing multiple results from a single sample are being able to accurately identify pathogens causing infection in a rapid fashion, the identification of co-infections and the identification of genetic drug resistance. If a patient presents with a wound that is not healing a physician will perform a culture in order to identify the pathogen or pathogens present. At this point the physician will often treat the symptoms empirically due to the multitude of pathogens that could be causing the infection.  If the patient is on antibiotics at the time the sample is taken for culture there is a very good chance the culture will be negative which leaves the physician to continue empiric treatment. If on the other hand the physician had obtained a sample to be performed by Tem-PCR up to 25 pathogens would be tested including genetic drug resistance providing the physician with definitive information leading to proper treatment.

Diatherix claims that the test is covered by most insurance companies.